Alcohol and the brain

1. Alcohol and the brain Prof. Hanan Hagar Dr. Ishfaq Bukhari Pharmacology Unit College of Medicine KSU

2. Alcohol: The mother of All Evils

3. Ethyl alcohol (ethanol) Ethyl alcohol (ethanol) is the most commonly abused drug in the world. Pharmacokinetics • is a small lipophilic molecule • readily crosses all biological membranes • Rapidly & completely absorbed from GIT • Has large Vd (distributed to all body tissues) • Crosses placenta and excreted in milk 3

4. Pharmacokinetics of ethanol • metabolized in gastric mucosa & liver. • Oxidation of ethanol to acetaldehyde via alcohol dehydrogenase or cyt-p450 (CYP2E1). • Acetaldehyde is converted to acetate via acetaldehyde dehydrogenase which also reduces NAD+ to NADH. • Acetate ultimately is converted to CO2 + water. • At low ethanol conc., minor metabolism by MEOS (microsomal ethanol-oxidizing system) mainly cyt-p450 (CYP2E1). Upon continuous alcohol use, this enzyme is stimulated and contribute significantly to alcohol metabolism.

5. Alcohol Metabolism; 90-98% metabolized in liver ADHALDH CH3CH2OH  CH3CHOCH3COOH Ethanol Acetaldehyde Acetic Acid

6. Cytosol NAD+ ER O2 ADH MEOS NADPH P450 NADH NADP+ NAD+ Mitochondrion AlDH NADH Disulfiram (antabuse) Chlorpropamide (diabetes) Extra-hepatic tissue EtOH Hepatic Cellular Processing Acetaldehyde Acetate

7. Hepatic Ethanol Metabolism Alcohol dehydrogenase RATE-LIMITING STEP Alcohol Acetaldehyde NADH NAD+ NAD+ Aldehyde dehydrogenase NADH Acetyl CoA Acetate Citric Acid Cycle Energy Fatty liver Fatty Acid synthesis 7

8. Pharmacokinetics of ethanol • Acute alcohol consumption inhibits liver enzymes CYP450 2E1, so decrease metabolism of other drugs taken concurrently as (warfarin, phenytoin). • Chronic alcohol consumption induces CYP450 2E1, which leads to significant increases in ethanol metabolism (Tolerance) & metabolism of other drugs as warfarin.

9. Genetic variation of alcohol metabolism Aldehyde Dehydrogenase polymorphism • Asian populations have genetic variation in aldehyde dehydrogenase. • They metabolized alcohol at slower rate than other populations. • Can develop “Acute acetaldehyde toxicity” after alcohol intake characterized by nausea, vomiting, dizziness, vasodilatation, headache and facial flushing.

10. Alcohol excretion • Excreted unchanged in urine (2-8%). • Excretion unchanged via lung (basis for breath alcohol test). • Rate of elimination is zero-order kinetic (not concentration-dependent) i.e. rate of elimination is the same at low and high concentration.

11. Mechanism of action of alcohol • is a CNS depressants • Acute alcohol causes: • Enhancement the effect of GABA (inhibitory neurotransmitter) on its GABA receptors in brain leading to CNS depression • Inhibition of glutamate action (excitatory neurotransmitter) on NMDA receptors leading to disruption in memory, consciousness, alertness. 11

12. Chronic alcohol leads to up-regulation of NMDA receptors & voltage sensitive Ca channels (Ca influx to nerve cells) leading to alcohol tolerance & withdrawal symptoms(tremors, exaggerated response & seizures).

13. Acute actions of alcohol: In mild-moderate amounts CNS depression • relieves anxiety, euphoria (feeling of well-being). • slurred speech, impaired judgment, ataxia • Sedation, hypnosis, loss of consciousness • In huge amounts, severe CNS depression (respiratory depression, respiratory acidosis, pulmonary aspiration, coma. CVS depression • Myocardial contractility depression • Vasodilatation due to vasomotor center depression & direct smooth muscle relaxation caused by acetaldehyde. 13

14. Acute actions of ethanol : In severe amounts • Severe CNS depression • Nausea, vomiting, aspiration of vomitus. • Respiratory depression. • CVS depression • Volume depletion • Hypotension • Hypothermia • Coma, death.

15. Chronic ethanol abuse (alcoholism) is associated with many complications • Tolerance, dependence, addiction, behavioral changes • Liver: hepatic cirrhosis & liver failure. • CVS: hypertension, myocardial infarction • CNS: cerebellar degeneration, and peripheral neuropathy. Wernicke encephalopathy or Korsakoff psychosis may occur. • GIT system: irritation, inflammation, bleeding, nutritional deficiencies • Endocrine system: gynecomastia & testicular atrophy • Hematological disorders, neoplasia.

16. Chronic alcohol use (Alcoholism) Liver The most common medical complication • Reduction of gluconeogenesis • Fatty liver/ alcoholic steatosis • Hepatitis • Hepatic cirrhosis: jaundice, ascites, bleeding, encephalopathy. • Irreversible liver failure.

17. Healthy Liver Liver in chronic alcoholics

18. Healthy Liver vsFatty Liver Normal liver Fatty liver Acetaldehyde is more toxic than alcohol causing mild inflammation and fat cell proliferation

19. Alcoholic Liver Disease Normal Steatosis Cirrhosis Steatohepatitis

20. Gastrointestinal system • Gastritis, hemorrhagic esopahgitis, ulcer diseases, pancreatitis (due to direct toxic action on epithelium) • Diarrhea • Deficiency of vitamins. • Exacerbates nutritional deficiencies • weight loss, and malnutrition

21. Alcoholism Cardiovascular System Chronic alcohol abuse can lead to cardiomyopathy • Cardiac hypertrophy • Congestive heart failure. • Arrhythmia (due to potassium and magnesium depletion) • Hypertension: due to increased calcium & sympathetic activity.

22. Hematological complications: • Iron deficiency anemia(due to inadequate dietary intake & GIT blood loss). • Megaloblastic anemia: (due to folate deficiency, malnutrition, impaired folate absorption). • Hemolytic anemia. • Bone marrow suppression • Thrombocytopenia(suppressing platelet formation, prolong bleeding times). • Impaired production of vitamin-K dependent clotting factorsleading to prolonged prothrombin time.

23. Fetal Alcohol Syndrome: Irreversible • Ethanol rapidly crosses placenta • Pre-natal exposure to alcohol causes: - Intrauterine growth retardation (due to hypoxia) • Congenital malformation(teratogenesis): • Microcephaly • Impaired facial development • Congenital heart defects • Physical and mental retardation.

24. Fetal Alcohol Syndrome ( FAS )

25. Endocrine system: • Hypogonadism: In women: ovarian dysfunction, amenorrhea, anovulation, hyperprolactinemia, infertility. In men: gynecomastia, decreased muscle & bone mass, testicular atrophy, sexual impotence due to inhibition of luteinizing hormone (LH) , decrease in testosterone, estradiol, progesterone. • Hypoglycemia & ketoacidosis due to impaired hepatic gluconeogenesis & excessive lipolytic factors, especially increased cortisol and growth hormone.

26. Central Nervous System • Tolerance • Physiological and psychological dependence • Addiction: dopamine, serotonin and opioids are involved. • Neurologic disturbances • Wernicke-Korsakoff syndrome

27. Wernicke-Korsakoff syndrome It is a combined manifestation of 2 disorders: Wernicke's encephalopathy: characterized by • ocular disturbances - unsteady gait • changes in mental state as confusion, delirium, ataxia Korsakoff's psychosis: impaired memory & cognitive and behavioral dysfunction. Cause: thiamine (vitamin B1) deficiencydue to: • inadequate nutritional intake • decreased uptake of thiamine from GIT • decreased liver thiamine stores Treated by: thiamine + dextrose-containing IV fluids.

28. Alcoholism Tolerance Chronic consumption of alcohol leads to tolerance That develops due to: Metabolic tolerance (pharmacokinetic): due to induction of liver microsomal enzymes. Functional tolerance (Pharmacodynamic): due to change in CNS sensitivity.

29. Alcoholism withdrawal symptoms • Autonomic hyperactivity & craving for alcohol • Vomiting, thirst • Profuse sweating, severe tachycardia • Vasodilatation, fever • Delirium, tremors, anxiety, agitation, insomnia • transient visual/ auditory illusions, violent behavior, hallucinations. • Grand mal seizures(after 7-48 hr alcohol cessation) • Due to super-sensitivity of glutamate receptors & hypoactivity of GABA receptors are possibly involved.

30. Management of alcoholism withdrawal • Substituting alcohol with a long-acting sedative hypnotic drug then tapering the dose. • Benzodiazepines as (chlordiazepoxide, diazepam) or lorazepam that is preferable (shorter duration of action). • Efficacy: IV/ po • Manage withdrawal symptoms & prevent irritability, insomnia, agitation & seizures. • Dose of BDZs should be carefully adjusted to provide efficacy & avoid excessive dose that causes respiratory depression & hypotension.

31. Fluoxetine • Clonidine & Propranolol: inhibits the action of exaggerated sympathetic activity • Acamprosate: a weak NMDA receptor antagonist & GABA activator, reduce psychic craving.

32. To prevent alcohol relapse: Disulfiram therapy: 250 mg daily • blocks hepatic aldehyde dehydrogenase, this will increase blood level of acetaldehyde. • Acetaldehyde produces extreme discomfort, vomiting, diarrhea, flushing, hotness, cyanosis, tachycardia, dyspnea, palpitations & headache. • Disulfiram-induced symptoms render alcoholics afraid from drinking alc.

33. Alcohol and drug interactions • Acute alcohol use causes inhibition of liver enzyme, decreases metabolism of some drugs and increases their toxicities e.g. bleeding with warfarin • Chronic alcohol use induces liver microsomal enzymes and increases metabolism of drugs such as warfarin, propranolol andetc • Alcohol suppresses gluconeogenesis, which may increase risk for hypoglycemia in diabetic patients.

34. NSAIDs + alcohol: Increase in the risk of developing a major GI bleed or an ulcer. • Acetaminophen + alcohol (chronic use): risk of hepatotoxicity. Alcohol can • Narcotic drugs (codeine and methahdone) + alcohol: risk of respiratory and CNS depression.